Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation

Franzke, Claus Werner; Cobzaru, Cristina; Triantafyllopoulou, Antigoni; Löffek, Stefanie; Horiuchi, Keisuke; Threadgill, David W.; Kurz, Thomas; Rooijen, Nico van; Bruckner‐Tuderman, Leena; Blobel, Carl P.

doi:10.1084/jem.2011225820913c

Cited by 14 publications

(16 citation statements)

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“…IL-36α, IL-36β, and IL-36γ can induce IL-17 and TNF expression in keratinocytes, which can be synergized by the cytokine IL-22 (Carrier et al, 2011). Furthermore, several reports indicate that epidermal growth factor signaling regulates the expression of IL-36α and IL-36β in the skin (Yang et al, 2010; Franzke et al, 2012) suggesting an important role of the agonists IL-36α and IL-36β in skin homeostasis. In line with this is the observation that transgenic mice which overexpress the IL-36α gene in basal keratinocytes display acanthosis and hyperkeratosis of the skin, which are characteristics of psoriatic skin lesions (Blumberg et al, 2007).…”

Section: The Il-36 Subfamilymentioning

confidence: 99%

New Insights in the Immunobiology of IL-1 Family Members

Veerdonk¹,

Netea²

2013

Front. Immunol.

137

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The interleukin-1 (IL 1) family of ligands is associated with acute and chronic inflammation, and plays an essential role in the non-specific innate response to infection. The biological properties of IL 1 family ligands are typically pro-inflammatory. The IL 1 family has 11 family members and can be categorized into subfamilies according to the length of their precursor and the length of the propiece for each precursor (Figure 1). The IL 1 subfamily consists of IL 1α, IL 1β, and IL 33, with the longest propieces of the IL 1 family. IL 18 and IL 37 belong to the IL 18 subfamily and contain smaller propieces than IL 1 and IL-33. Since IL 37 binds to the IL 18Rα chain it is part of the IL 18 subfamily, however it remains to be elucidated how the propiece of IL 37 is removed. IL 36α, β, and γ as well as IL 36 Ra belong to the IL 36 subfamily. In addition, IL 38 likely belongs to this family since it has the ability to bind to the IL 36R. The IL 36 subfamily has the shortest propiece. The one member of the IL 1 family that cannot be categorized in these subfamilies is IL 1 receptor antagonist (IL 1Ra), which has a signal peptide and is readily secreted. In the present review we will describe the biological functions of the IL-1F members and new insights in their biology.

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Section: The Il-36 Subfamilymentioning

confidence: 99%

New Insights in the Immunobiology of IL-1 Family Members

Veerdonk¹,

Netea²

2013

Front. Immunol.

137

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“…12 Although it has been shown that specific pharmacologic inhibition of ADAM17 can reduce clinical signs of chemically induced colitis, 13 there are substantial concerns about therapeutically targeting ADAM17 due to its essential role in protecting the skin and intestinal barrier through activating the EGFR pathway. 14 Indeed, in a dextran sulfate sodium (DSS) mouse model of colitis, mice hypomorphic for Adam17 were highly susceptible to intestinal damage. Disease could be overcome by TGFA-mediated activation of the EGFR pathway, thus pointing to a function of ADAM17 in preserving the intestinal barrier.…”

Section: Introductionmentioning

confidence: 99%

Loss of RHBDF2 results in an early-onset spontaneous murine colitis

Geesala

Schanz

Biggs

et al. 2019

Journal of Leukocyte Biology

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Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation‐mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane‐bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10−/−/Rhbdf2−/− mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10−/−/Rhbdf2−/− mice correlated with a dysbiotic gut microbiota and elevated Th1‐associated immune responses with increased interferon gamma and IL2 production. In addition, Il10−/−/Rhbdf2−/− mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2−/− mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium‐induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.

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“…oral keratinocytes) actively participate in immune responses and inflammation by secreting a variety of cytokines, chemokines, growth factors and neuropeptides in response to biological, chemical and mechanical stimulation in the oral cavity (23,24). Keratinocytes are thought to participate in the regulation of the immune response through the enzymatic action of various metalloendopeptidases, including NEP, ECE and ADAMs, which cleave bioactive peptides such as chemokines, cytokines and neuropeptides, thus affecting their activity and specificity (25)(26)(27)(28). In oral keratinocytes, these metalloendopeptidases may also regulate biological activities throughout the progression of oral diseases.…”

Section: Discussionmentioning

confidence: 99%

“…ADAM17 is ubiquitously expressed and cleaves membrane proteins, such as EGFR ligands, L-selectin and TNF-a, from the surface, thus regulating responses to tissue injury and inflammation. A recent study identified a critical role of the ADAM17-EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggested that this pathway could represent a good target for the treatment of epidermal barrier defects (28). Until now, there has been no report on the ADAM17 levels in the oral mucosal epithelium, whilst recent studies reported that an increased level of TNF-a-converting enzyme (ADAM17) in the gingival crevicular fluid of patients with periodontitis may be associated with alveolar bone loss and worsening of the outcome of periodontitis (19,38).…”

Section: Discussionmentioning

confidence: 99%